JP6471103B2 - ヒスタミンｈ４受容体のベンゾイミダゾール−２−イルピリミジンモジュレータ - Google Patents
ヒスタミンｈ４受容体のベンゾイミダゾール−２−イルピリミジンモジュレータ Download PDFInfo
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- JP6471103B2 JP6471103B2 JP2015561646A JP2015561646A JP6471103B2 JP 6471103 B2 JP6471103 B2 JP 6471103B2 JP 2015561646 A JP2015561646 A JP 2015561646A JP 2015561646 A JP2015561646 A JP 2015561646A JP 6471103 B2 JP6471103 B2 JP 6471103B2
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- hemitartrate
- tetrahydrate
- autoimmune
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|---|---|---|---|---|
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| WO2002078701A1 (fr) | 2001-03-30 | 2002-10-10 | Smithkline Beecham Corporation | Utilisation de pyrazolopyridines comme composes therapeutiques |
| ATE409181T1 (de) | 2001-05-08 | 2008-10-15 | Univ Yale | Proteomimetische verbindungen und verfahren |
| AR035543A1 (es) | 2001-06-26 | 2004-06-16 | Japan Tobacco Inc | Agente terapeutico para la hepatitis c que comprende un compuesto de anillo condensado, compuesto de anillo condensado, composicion farmaceutica que lo comprende, compuestos de benzimidazol, tiazol y bifenilo utiles como intermediarios para producir dichos compuestos, uso del compuesto de anillo con |
| PL369738A1 (en) * | 2001-11-05 | 2005-05-02 | Merck Patent Gmbh | Hydrazono-malonitriles |
| US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
| US7148236B2 (en) | 2002-01-17 | 2006-12-12 | Merck & Co., Inc. | Modulators of acetylcholine receptors |
| TWI270542B (en) | 2002-02-07 | 2007-01-11 | Sumitomo Chemical Co | Method for preparing sulfone or sulfoxide compound |
| US7314937B2 (en) | 2002-03-21 | 2008-01-01 | Eli Lilly And Company | Non-imidazole aryl alkylamines compounds as histamine H3 receptor antagonists, preparation and therapeutic uses |
| ATE425753T1 (de) | 2002-08-02 | 2009-04-15 | Genesoft Pharmaceuticals Inc | Biaryl-verbindungen mit antiinfektiver wirkung |
| US20040127395A1 (en) | 2002-09-06 | 2004-07-01 | Desai Pragnya J. | Use of histamine H4 receptor modulators for the treatment of allergy and asthma |
| EP1543011B1 (fr) | 2002-09-06 | 2006-05-03 | Janssen Pharmaceutica N.V. | Derives de thienopyrrole et de furannopyrolle et leur utilisation comme ligands du recepteur histaminique h4 |
| WO2004022060A2 (fr) | 2002-09-06 | 2004-03-18 | Janssen Pharmaceutica, N.V. | Composes heterocycliques |
| PL375964A1 (en) | 2002-09-06 | 2005-12-12 | Janssen Pharmaceutica, N.V. | Use of indolyl derivatives for the manufacture of a medicament for the treatment allergic rhinitis |
| JP2006510597A (ja) | 2002-09-27 | 2006-03-30 | メルク エンド カムパニー インコーポレーテッド | 置換ピリミジン類 |
| TW200501960A (en) | 2002-10-02 | 2005-01-16 | Bristol Myers Squibb Co | Synergistic kits and compositions for treating cancer |
| US20040105856A1 (en) | 2002-12-02 | 2004-06-03 | Robin Thurmond | Use of histamine H4 receptor antagonist for the treatment of inflammatory responses |
| MXPA05011710A (es) | 2003-05-05 | 2006-01-23 | Hoffmann La Roche | Derivados de pirimidina con actividad de crf. |
| WO2004110350A2 (fr) | 2003-05-14 | 2004-12-23 | Torreypines Therapeutics, Inc. | Composes et leurs utilisations pour la modulation de l'amyloide-beta |
| SE0302116D0 (sv) * | 2003-07-21 | 2003-07-21 | Astrazeneca Ab | Novel compounds |
| KR20060056377A (ko) | 2003-08-13 | 2006-05-24 | 카이론 코포레이션 | Ｇｓｋ-3 억제제 및 그것의 사용 |
| WO2005028447A1 (fr) | 2003-09-22 | 2005-03-31 | S*Bio Pte Ltd | Derives de benzimidazole: preparation et compositions pharmaceutiques |
| KR20060111466A (ko) | 2003-09-30 | 2006-10-27 | 얀센 파마슈티카 엔.브이. | 퀴녹살린 화합물 |
| RU2006110561A (ru) | 2003-09-30 | 2007-10-10 | Янссен Фармацевтика Н.В. (Be) | Соединения бензоимидазола |
| US7115646B2 (en) | 2003-10-08 | 2006-10-03 | Bristol Myers Squibb, Co. | Cyclic diamines and derivatives as factor Xa inhibitors |
| US20070099938A1 (en) | 2003-10-24 | 2007-05-03 | Ono Pharmaceutical Co., Ltd. | Antistress drug and medical use thereof |
| US8277831B2 (en) | 2004-02-17 | 2012-10-02 | Advanced Technologies And Regenerative Medicine, Llc. | Drug-enhanced adhesion prevention |
| AU2005226729B2 (en) | 2004-03-25 | 2010-01-28 | Janssen Pharmaceutica N.V. | Imidazole compounds |
| JPWO2005115993A1 (ja) | 2004-05-31 | 2008-03-27 | 萬有製薬株式会社 | キナゾリン誘導体 |
| ES2362102T3 (es) | 2004-06-30 | 2011-06-28 | Janssen Pharmaceutica Nv | Eteres de bencimidazol e imidazopiridina sustituidos con arilo como agentes anticáncer. |
| AU2005278292B2 (en) | 2004-08-31 | 2011-09-08 | Msd K.K. | Novel substituted imidazole derivatives |
| WO2006042102A2 (fr) | 2004-10-05 | 2006-04-20 | Neurogen Corporation | Composes de pyrrolo-pyridine, de pyrrolo-pyrimidine et composes heterocycliques apparentes |
| US7381732B2 (en) | 2004-10-26 | 2008-06-03 | Bristol-Myers Squibb Company | Pyrazolobenzamides and derivatives as factor Xa inhibitors |
| JP5086809B2 (ja) | 2004-12-17 | 2012-11-28 | メルク カナダ インコーポレイテッド | ｍＰＧＥＳ−１阻害剤としての２−（フェニルまたはヘテロ環式）−１Ｈ−フェナントロ［９，１０−ｄ］イミダゾール |
| US7442716B2 (en) | 2004-12-17 | 2008-10-28 | Merck Frosst Canada Ltd. | 2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors |
| WO2006102645A1 (fr) | 2005-03-24 | 2006-09-28 | Janssen Pharmaceutica, N.V. | Amides derives de biaryle modulateurs de recepteur vanilloide vr1 |
| WO2007044085A2 (fr) | 2005-05-19 | 2007-04-19 | Xenon Pharmaceuticals Inc. | Composes heteroaryle et leurs utilisations en tant qu'agents therapeutiques |
| NZ564222A (en) | 2005-06-14 | 2011-10-28 | Taigen Biotechnology Co Ltd | Pyrimidine compounds |
| US8193206B2 (en) | 2005-06-14 | 2012-06-05 | Taigen Biotechnology Co., Ltd. | Pyrimidine compounds |
| MX2007015675A (es) | 2005-07-04 | 2008-02-20 | Novo Nordisk As | Antagonistas del receptor de histamina h3. |
| CA2622372A1 (fr) | 2005-09-13 | 2007-03-22 | Palau Pharma, S.A. | Derives de 2-aminopyrimidine en tant que modulateurs de l'activite du recepteur h4 de l'histamine |
| AR056560A1 (es) | 2005-10-06 | 2007-10-10 | Astrazeneca Ab | Pirrolopiridinonas como moduladores cb1 |
| JP5301999B2 (ja) | 2005-10-31 | 2013-09-25 | メルク・シャープ・アンド・ドーム・コーポレーション | Ｃｅｔｐ阻害薬 |
| WO2007063935A1 (fr) | 2005-12-02 | 2007-06-07 | Mitsubishi Tanabe Pharma Corporation | Compose aromatique |
| CA2643562A1 (fr) | 2006-02-24 | 2007-08-30 | Anh Chau | 1h-phenanthro[9,10-d]imidazoles substitues en 2 par un phenyle ou un heterocycle |
| DE602007008859D1 (de) | 2006-03-31 | 2010-10-14 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyridine als modulatoren des histamin-h4-rezeptors |
| PL2007752T3 (pl) | 2006-03-31 | 2011-02-28 | Janssen Pharmaceutica Nv | Benzoimidazol-2-ilopirymidyny i pirazyny jako modulatory receptora histaminowego H4 |
| EP2010172B1 (fr) | 2006-04-07 | 2012-08-29 | Janssen Pharmaceutica N.V. | Indoles et benzoimidazoles modulateurs du récepteur de l'histamine h4 |
| WO2007120690A2 (fr) | 2006-04-10 | 2007-10-25 | Janssen Pharmaceutica N.V. | Thérapie combinée avec des antagonistes des récepteurs histaminiques h1r et h4r pour le traitement du prurit |
| US20090192158A1 (en) | 2006-05-02 | 2009-07-30 | Stacia Kargman | Methods for Treating or Preventing Neoplasias |
| JP2009537460A (ja) | 2006-05-18 | 2009-10-29 | メルク フロスト カナダ リミテツド | ｍＰＧＥＳ−１阻害剤としてのフェナントレン誘導体 |
| KR20090028819A (ko) | 2006-07-11 | 2009-03-19 | 얀센 파마슈티카 엔.브이. | 히스타민 ｈ４ 수용체의 벤조푸로- 및 벤조티에노피리미딘 조절제 |
| US8779154B2 (en) | 2006-09-26 | 2014-07-15 | Qinglin Che | Fused ring compounds for inflammation and immune-related uses |
| CL2008000467A1 (es) | 2007-02-14 | 2008-08-22 | Janssen Pharmaceutica Nv | Compuestos derivados de 2-aminopirimidina, moduladores del receptor histamina h4; su procedimiento de preparacion; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar un trastorno inflamatorio seleccionado de alegia, asma |
| WO2009068512A1 (fr) | 2007-11-30 | 2009-06-04 | Palau Pharma, S. A. | Dérivés de 2-aminopyrimidine en tant qu'antagonistes d'histamine h4 |
| WO2009079001A1 (fr) | 2007-12-18 | 2009-06-25 | Janssen Pharmaceutica N.V. | Imidazoles bicycliques substitué par hétéroaryle constituant des modulateurs du récepteur de l'histamine h4 |
| MX2010013727A (es) | 2008-06-12 | 2011-01-14 | Janssen Pharmaceutica Nv | Uso de un antagonista h4 de histamina para el tratamiento de adherencias postoperatorias. |
| MX2010013726A (es) | 2008-06-12 | 2011-01-14 | Janssen Pharmaceutica Nv | Moduladores de diamino-piridina, pirimidina, y piridazina del receptor h4 de histamina. |
| TWI498326B (zh) | 2008-06-30 | 2015-09-01 | Janssen Pharmaceutica Nv | 用於製備經取代之嘧啶衍生物之化合物 |
| US20100029942A1 (en) | 2008-06-30 | 2010-02-04 | Sergio Cesco-Cancian | Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives |
| US8852569B2 (en) * | 2008-08-28 | 2014-10-07 | The General Hospital Corporation | Prevention and treatment of itch with cysteine protease inhibition |
| IT1395963B1 (it) * | 2009-06-04 | 2012-11-02 | Rottapharm Spa | Forme cristalline di 6-(1h-imidazol-1-il)-2-fenil chinazolina e dei suoi sali |
| TWI519533B (zh) | 2010-11-01 | 2016-02-01 | Ｌｇ生命科學有限公司 | １－｛（２Ｓ）－２－胺基－４－［２，４－雙（三氟甲基）－５，８－二氫吡啶并［３，４－ｄ］嘧啶－７（６Ｈ）－基］－４－側氧丁基｝－５，５－二氟哌啶－２－酮酒石酸鹽之水合物 |
| EP2465498A1 (fr) | 2010-11-23 | 2012-06-20 | Faes Farma, S.A. | Dérivés d'amine diphényl : utilisations, procédés de synthèse et compositions pharmaceutiques |
| SMT202000084T1 (it) | 2013-03-06 | 2020-03-13 | Janssen Pharmaceutica Nv | Modulatori benzoimidazol-2-il pirimidinici del recettore h4 dell'istamina |
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